Clinical Center for ChiLDREN: Pathogenesis, Biomarkers, and Antifibrotic Therapy

描述（由申请人提供）：儿童肝病研究和教育网络（ChiLDREN）为改善严重肝病儿童的生活提供了前所未有的机会。该临床中心继续做出富有成效的贡献， ChiLDREN提出了三个主要目标：I。联合体贡献：一个组织良好的基础设施，使高水平的患者招募和数据和标本收集得到了很好的建立，整合到美国最大的儿科肝病学项目之一，拥有经验丰富的研究者和协调员，以及在临床研究中的良好记录。此外，我们建议对临床数据和胆道闭锁肝组织进行分析，以更好地评估表型和临床病理学相关性，并通过竞争结局、多变量和神经网络建模，更好地预测和确定肝门静脉吻合术后的结局。二.辅助研究：几项独特的研究与这一提议有关，从该临床中心的卓越优势和初步研究发展而来：（i）将进一步评估血清纤维化和新的成像标志物，以改善诊断和监测ChiLDREN疾病中的肝纤维化;（ii）在平行的机制研究中，我们正在进一步探索胆道闭锁和CFLD发病机制的分子机制，研究表观遗传学，遗传学，以及肝组织和血清中的基本纤维发生机制，我们建议将这些研究扩展到储存库组织和数据分析。三.临床试验：为了评价新的抗纤维化疗法，正在患有新诊断的BA的婴儿中进行pentoxyfilline（PTX）（一种已知的在婴儿中被证明安全的抗纤维化治疗剂）的II期临床试验（在clinical www.example.com注册trials.gov），以确定PTX是否具有针对BA的足够生物活性，具有最小的风险，这需要进一步研究。我们假设PTX是一种安全有效的治疗药物，可以改善某些进行性胆汁性纤维化/肝硬化儿童的预后。由于目前没有有效的 为了研究CHiLDREN疾病的药物治疗，适当探索这种药物的安全性和有效性将完全符合ChiLDREN的职责，该公司独特地准备大规模研究这种新疗法。我们希望为实现ChiLDREN的所有目标做出新的贡献，帮助肝病儿童。我们希望提供高价值的参与，利用完善的ChiLDREN血清和组织库寻找非侵入性生物标志物和更好的预后预测，开始对这些疾病的分子发病机制进行富有成效的机制研究，并帮助领导新的安全疗法的研究，以帮助填补目前的治疗空白。

DESCRIPTION (provided by applicant): The Childhood Liver Disease Research and Education Network (ChiLDREN) provides an unprecedented opportunity to improve the lives of children with serious liver diseases. Continued productive contributions of this Clinical Center to ChiLDREN are proposed with 3 major aims: I. Consortium Contribution: A well-organized infrastructure that enables a high level of patient enrollment and data and specimen collection is well established, integrated into one of the largest pediatric hepatology programs in the United States with experienced investigators and coordinators, and an excellent track record in clinical research. In addition, we propose leading an analysis of clinical data and biliary atresia liver tissue to better evaluate phenotypic and clinicopathological correlations and, by competing outcomes, multivariate and neural network modeling, to better predict and determine outcomes after hepatoportenterostomy. II. Ancillary Studies: Several unique studies are linked to this proposal, developing from this Clinical Center's pre-eminent strengths and preliminary studies: (i) serum fibrosis and novel imaging markers will be further evaluated to improve diagnosis and monitor liver fibrosis in ChiLDREN diseases; (ii) in parallel mechanistic studies, we are further exploring the molecular mechanisms of pathogenesis of biliary atresia and CFLD, studying epigenetic, genetic, and fundamental fibrogenetic mechanisms in liver tissue and serum, and we propose extending these studies to repository tissue and data analysis. III. Clinical Trial: To evaluate new antifibrogenic therapies, a Phase II clinical trial of pentoxyfilline (PTX), a known antifibrogenic antiinflammatory agent of proven safety in infants, is being conducted in infants with newly-diagnosed BA (registered with clinical trials.gov) to determine whether PTX has sufficient biological activity against BA, with minimal risk, which warrants further study. We hypothesize that PTX will be a safe and effective therapeutic agent to improve outcomes for select children with progressive biliary fibrosis/cirrhosis. Since there are currently no effective medical therapies for CHiLDREN diseases, proper exploration of the safety and efficacy of this agent would perfectly fit within the charge of ChiLDREN, which is uniquely poised to examine such novel therapies on a large scale. We hope to renew our productive contribution to achieving all the aims of ChiLDREN, helping to make a difference for children with liver diseases. We expect to provide high-value participation, capitalize on the well- developed ChiLDREN serum and tissue repository in the search for non-invasive biomarkers and better prediction of outcomes, embark upon fruitful mechanistic studies on the molecular pathogenesis of these diseases, and help lead investigations of novel safe therapies to help fill the current therapeutic void.